WO2015051252A1 - Compositions et méthodes destinées à traiter les cancers ayant une activité jak2 - Google Patents

Compositions et méthodes destinées à traiter les cancers ayant une activité jak2 Download PDF

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WO2015051252A1
WO2015051252A1 PCT/US2014/059045 US2014059045W WO2015051252A1 WO 2015051252 A1 WO2015051252 A1 WO 2015051252A1 US 2014059045 W US2014059045 W US 2014059045W WO 2015051252 A1 WO2015051252 A1 WO 2015051252A1
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inhibitor
jak2
subject
akt
erk
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PCT/US2014/059045
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Kris Cameron WOOD
Peter Saville WINTER
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Duke University
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Priority to US15/027,216 priority Critical patent/US10111897B2/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/91—Transferases (2.)
    • G01N2333/912—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
    • G01N2333/91205—Phosphotransferases in general
    • G01N2333/9121—Phosphotransferases in general with an alcohol group as acceptor (2.7.1), e.g. general tyrosine, serine or threonine kinases
    • G—PHYSICS
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    • G01N2800/7023—(Hyper)proliferation
    • G01N2800/7028—Cancer

Definitions

  • MPN Myeloproliferative neoplasms
  • CML chronic myeloid leukemia
  • PV polycythaemia vera
  • ET essential thrombocythaemia
  • PMF primary myelofibrosis
  • JAK/STAT signaling has been described in a subset of patients that do not harbor JAK mutations (see, e.g., Quintas-Cardanarn A. et al. 2013, Clinical Cancer Res. Dok lQ.l 158/1078-0432.CCR- 12*0284). Taken together, evidence to date supports the targeting of the JAK STAT pathway , specifically JAK2, in patients with various MPNs.
  • Treatment failures seen in the clinic could be due to: ( 1 ) second site mutations in the kinase domain (see, e.g., Deshpande, A. et al. 201 1 , Leukemia 26:708); (2) heterodimerization of activated JAK.2 and JAKl or TYK2, leading to reactivation of signaling to downstream STAT proteins (see, e.g., Koppikar, P. et al.
  • the present disclosure relates to our surprising disclovery that in certain cancers conventionally treated with JAK inhibitors, combined inhibition of JAK2 and Ras effector pathways, or the direct, selective inhibitio of BCL-XL protein, yields more robust and durable responses than JAK inhibitor monotherapy.
  • the disclosure encompasses a method of treating cancer in a subject in need thereof.
  • the method includes the step of administering to the subject an effective amount of (a) an AKT and/or PI3K inhibitor; (b) an ERK7MEK inhibitor; (c) a BCL- XL protein inhibitor; or (d) any combination thereof; whereby the cancer is successfully treated.
  • the AKT and/or PI3K inhibitor is AZD5363, VQD-002,
  • the ERK/MEK inhibitor is Trametinib, Selumetinib,
  • the BCL-XL protein inliibitor is ABT-737, ABT-263,
  • ABT-199 Genasense, obatoclax, or combinations thereof.
  • the cancer is a myelproliferative neoplasm
  • myelproliferative neoplasms include chronic myeloid leukemia (CML), acute myeloid leukemia (AML), polycythaemia vera (PCV), essential thrombocythaemia (ET), primary myelofibrosis (PMF), chronic eosinophilic leukemia (CEL), chronic myelomonocytic leukemia (CMML), systemic mastocytosis (SM), idiopathic myelofibrosis (IMF), and myeloma.
  • CML chronic myeloid leukemia
  • AML acute myeloid leukemia
  • PCV polycythaemia vera
  • E essential thrombocythaemia
  • PMF primary myelofibrosis
  • CEL chronic eosinophilic leukemia
  • CMML chronic myelomonocytic leukemia
  • SM systemic
  • the cancer is resistant to JA 2 inhibitor-based therapy.
  • the subject has an activated AKT pathway.
  • the cancer has a JAK2 V617i mutation.
  • the method furthe includes the step of administering a
  • JAK2 inhibitor to the subject.
  • JAK2 inhibitors include without limitation
  • the AKT and/or PI3K inhibitor, the ERK/MEK inhibitor, the BCL-XL protein inhibitor, or any combination thereof is administered before or concurrently with the JAK2 inhibitor.
  • both the AKT and/or PI3K inliibitor and the ERK/MEK inhibitor are administered.
  • the BCL-XL protein inliibitor is administered and no JAK2 inhibitor is administered.
  • no AKT and/or PI3K inhibitor and no ERK/MEK inhibitor is administered.
  • the disclosure encompasses an AKT and/or PI3K inhibitor for use in treating cancer.
  • AKT and/or PI3K inhibitors include without limitation AZD5363, VQD-002, Perifosine, Wortmannin, demthozyviridin, LY294002, CALl Ol, PX-866, IPI-145, BAY 80-6946, BEX235, RP6503, TOR 1202, SF1 126, INKl 1 17, GDC-0941 ,
  • BKMI20 BKMI20, XL147, XL765, Paloroid 529, GSK1059615, ZSTK474, PWT33597, 1C871 14, TGlOO-115, CAL263, RP6530, PI-103, GNB-477, CUDC-907, AEZS-136, and combinations thereof.
  • the disclosure encompasses an ERK/MEK inhibitor for use in treating cancer.
  • ERK/MEK inhibitors include without limitation Trametinlb, Selumetinib, MEK162, PD-325901 , XL518, CI-1040, PD035901 , and combinations thereof.
  • the disclosure encompasses a BCL-XL protein inhibitor for use
  • Exemplar BCL-X L protein inhibitors include without limitation ABT-737, ABT-263, ABT-199, Genasense, obatoclax, and combinations thereof.
  • the cancer is a myelproliferative neoplasm.
  • Exemplary myelproliferative neoplasms include without limtation chronic myeloid leukemia (CML), acute myeloid leukemia (AML), polycythaemia vera (PCV), essential thrombocythaemia (ET), primary myelofibrosis (PMF), chronic eosinophilic leukemia (CEL), chronic myelomonocytic leukemia (CMML), systemic mastocytosis (SM), idiopathic myelofibrosis (IMF), and myeloma.
  • CML chronic myeloid leukemia
  • AML acute myeloid leukemia
  • PCV polycythaemia vera
  • E essential thrombocythaemia
  • PMF primary myelofibrosis
  • CEL chronic eosinophilic leukemia
  • CMML chronic myelomonocytic leukemia
  • SM systemic mastocytosis
  • IMF idi
  • the cancer includes a JAK2 V617 mutation
  • the use of the inhibitor includes co-administering a JAK2 inhibitor.
  • JAK2 inhibitors include without limitation INCB018424/Ruxolitinib, Tofacitinub, Baricitnib, CYT387, Lestaurtinib, Pacritinib, TGI 01348, and combinations thereof.
  • the use of the BCL-XL protein inhibitor does not include co-administering a JAK2 inhibitor. In some embodiments, the use of the BCL-XL protein inhibitor does not include co-administering an AKT and or PI3K inhibitor or an ERK/MEK inhibitor.
  • the disclosure encompasses a composition including both an
  • AKT and/or PI3 inhibitor and an ERK/MEK inhibitor for use in treating cancer include without limitation AZD5363, VQD-002, Perifosine, Wortmannin, demthozyviridin, LY294002, CAL101 , PX-866, IPI-145, BAY 80-6946, ⁇ 235, RP6503, TGR 1202, SFl 126, INK1 1 17, GDC-0941 , BKM120, XL147, XL765, Palomid 529,
  • ERK/MEK inhibitors include without limitation Trametinib, Selumetinib, MEK162, PD-325901, XL518, CI- 1040, PD035901, and combinations thereof.
  • the cancer is a myelproliferative neoplasm.
  • myelproliferative neoplasms include without limitation chronic myeloid leukemia (CML), acute myeloid leukemia (AML), polycythaemia vera (PCV), essential thrombocythaemia (ET), primary myelofibrosis (PMF), chronic eosinophilic leukemia (CEL), chronic myelomonocytic leukemia (CMML,), systemic mastocytosis (SM), idiopathic myelofibrosis (IMF), and myeloma.
  • CML chronic myeloid leukemia
  • AML acute myeloid leukemia
  • PCV polycythaemia vera
  • E essential thrombocythaemia
  • PMF primary myelofibrosis
  • CEL chronic eosinophilic leukemia
  • CMML chronic myelomonocytic leukemia
  • the disclosure encompasses an AKT and/or PI3 inhibitor for use in manufacturing a medicament for treating cancer.
  • AKT and/or PI3K inhibitors include without limitation AZD5363, VQD-002, Perifosine, Wortmannln, demthozyviridin, LY294002, CALlOl, PX-866, IPI-145, BAY 80-6946, BEX235, RP6503, TOR 1202, SF1126, INK1 1 17, GDC-0941, BKM120, XL147, XL765, Palomid 529, GSK1059615, ZSTK474, PWT33597, 1C87114, TGI 00-115, CAL263, RP6530, PI-103, GNE-477, CUDC-907, AEZS- 136, and combinations thereof.
  • the disclosure encompasses an ERK/MEK inhibitor for use in manufacturing a medicament for treating cancer.
  • ERK/MEK inhibitors include without limitation Trametinib, Selumetinib, MEK162, P0-3259O1 , XL518, CI-1040, PDO35901 , and combinations thereof.
  • the disclosure encompasses a BCL-XL protein inhibitor for use in manufacturing a medicament for treating cancer.
  • BCL-XL protein inhibitors include without limitation ABT-737, ABT-263, ABT-199, Genasense, obatoclax, and
  • the cancer is a myelproliferative neoplasm.
  • myelproliferative neoplasms include without limitation chronic myeloid leukemia (CML), acute myeloid leukemia (AML), polycythaemia vera (PCV)j essential thrombocythaemia (ET), primary myelofibrosis (PMF), chronic eosinophilic leukemia (CEL), chronic myelomonoeytic leukemia (CMML), systemic mastocytosis (SM), idiopathic myelofibrosis (IMF), and myeloma.
  • CML chronic myeloid leukemia
  • AML acute myeloid leukemia
  • PCV polycythaemia vera
  • E essential thrombocythaemia
  • PMF primary myelofibrosis
  • CEL chronic eosinophilic leukemia
  • CMML chronic myelomonoeytic leukemia
  • the cancer is resistant to JAK2 inhibitor-based therapy.
  • the cancer has an activated AKT pathway.
  • the cancer includes a JAK2 V6!71' mutation.
  • the medicament is to be co-administered with a JAK2 inhibitor.
  • JAK2 inhibitors include without limitation INCB018424/Ruxolitinib, Tofaeitinub, Baricitnib, CYT387, Lestaurtinib, Pacritinib, TG101348, and combinations thereof.
  • the m edicament i s not to be coadministered with a J AK2 inhibitor.
  • the medicament is not to be co-administered with an AKT and/or PI3K inhibitor or an ERK/MEK inhibitor.
  • the disclosure encompasses a composition comprising both an
  • AKT and/or PI3K inhibitor and an ERK MEK inhibitor for use in manufacturing a medicament for treating cancer.
  • exemplary AKT and/or PI3K inhibitors include without limitation
  • AZD5363 VQD-002, Perifosine, Wortinannin, demthozyviridin, LY294002, CALlOl, PX-866, IPl-145, BAY 80-6946, BEX235, RP 503, TGR 1202, SF1 26, INKl 1 17, GDC-0941,
  • Exemplary ERK/ME inhibitors include without limitation Trametimb, Selumetinib, MEK162, PD-325901 , XL518, CM 040, PD035901 , and combinations thereof.
  • the cancer is a myelproliferative neoplasm.
  • myelproliferative neoplasms include without limitation chronic myeloid leukemia (CML), acute myeloid leukemia (AML), polyeyfhaemia vera (PCV), essential thrombocythaemia (ET), primary myelofibrosis (PMF), chronic eosinophilic leukemia (CEL), chronic myelomonocytic leukemia (CMML), systemic mastocytosis (SM), idiopathic myelofibrosis (IMF), and myeloma.
  • CML chronic myeloid leukemia
  • AML acute myeloid leukemia
  • PCV polyeyfhaemia vera
  • E essential thrombocythaemia
  • PMF primary myelofibrosis
  • CEL chronic eosinophilic leukemia
  • CMML chronic myelomonocytic leukemia
  • the diseosure encompasses a method of sensitizing a subject to a
  • the method includes the step of administering to the subject a therapeutically effective amount of an AKT and/or PI3K inhibitor in combination with the JAK2 inhibitor, whereby the subject is sensitized to the JAK2 inhibitor.
  • the AKT and/or PI3K inhibitor is administered before or concurrently with the JAK2 inhibitor.
  • Exemplary AKT and/or PI3K inhibitors include without limitation AZD5363 ,
  • the disclosure encompasses a method of sensitizing a subject to a JAK2 inhibitor wherein the subject has developed resistance to a JAK2 inhibitor- based therapy and has an activated ERK pathway.
  • the method includes the step of
  • the ERK/MEK inhibitor is administered before or concurrently with the JAK2 inhibitor
  • Exemplary ERK/MEK inhibitors include without limitation Trametinib,
  • the disclosure encompasses a method of sensitizing a subject to a JAK2 inhibitor wherein the subject has developed resistant to a JAK2 inhibitor-based therapy and has an activated ATK and ERK pathway.
  • the method includes the step of administering to the subject a therapeutically effective amount of an AKT and/or PI3 inhibitor and an ERK/MEK inhibitor in combination with the JAK2 inhibitor, whereby the subject is sensitized to the JAK2 inhibitor,
  • the AK and/or PI3K inhibitor and the ERK/MEK inhibitor are administered before or concurrently with the JAK2 inhibitor.
  • Exemplary AKT and/or PI3K inhibitors include without limitation AZD5363,
  • VQD-002 Perifosine, Wortmannin, demthozyviridin, LY294Q02, CAL101 , PX-866, IPI-145, BAY 80-6946, BEX235, RP6503, TOR 1202, SFl 126, INK!
  • Exemplary ERK/MEK inhibitors include without limitation include Trametinib, Selumetinib, MEK162, PD- 325901, XL518, CI-1040, PD035901 , and combinations thereof.
  • the disclosure encompasses a method of reversing resistance to JAK2 inhibitor therapy in a subject wherein the subject has an activated AKT pathway.
  • the method includes the step of administering to the subject a therapeutically effective amount of an AKT and/or PI3K inhibitor in combination with the JAK2 inhibitor, whereby the subject's resistance to JAK2 inhibitor therapy is reversed.
  • the AKT and/or PI3K inhibitor is administered before or concurrently with the JAK2 inhibitor.
  • Exemplary AKT and/or PI3K inhibitors include without limitation AZD5363,
  • the disclosure encompasses a method of reversing resistance to JAK2 inhibitor therapy in a subject wherein the subject has an activated ER ME pathway.
  • the method includes the ste of administering to the subject a therapeutically effective amount of an ERK/MEK. inhibitor in combination with the JAK2 inhibitor, whereby the subject's resistance to JAK2 inhibitor therapy is reversed.
  • the ERK/MEK inhibitor is administered before or concurrently with the JAK2 inhibitor.
  • Exemplary ERK MEK inhibitors include without limitation Trametinib,
  • the disclosure encompasses a method of reversing resistance to JAK2 inhibitor therapy in a subject wherein the subject has an activated AKT and ERK MEK pathway.
  • the method includes the step of administering to the subject a therapeutically effective amount of an AKT and/or PI3 inhibitor and an ERK MEK inhibitor in combination with the JAK2 inhibitor, whereby the subject's resistance to JAK2 inhibitor therapy is reversed.
  • the AKT and/or PI3 inhibitor and the ERK/MEK inhibitor are administered before or concurrently with the JAK2 inhibitor.
  • Exemplary AKT and/or PI3K inhibitors include without limitation AZD5363,
  • Exemplary ERK MEK inhibitors include without limitation Trametinib, Selumetinib, MEK162, PD-325901 , XL518, CI-1040, PD035901, and combinations thereof.
  • the disclosure encompasses a method of sensitizing a subject to a JAK2 inhibitor wherein the subject has developed resistance to a JAK2 inhibitor-based therapy and has at least one phosphorylated BAD- and/or activated BCL-XL protein.
  • the method includes the step of administering to the subject a therapeutically effective amount of a BCL-XL protein inhibitor in combination with the JAK2 inhibitor, whereby the subject is sensitized to the J AK2 inhibitor.
  • the disclosure encompasses a method of reversing resistance to JAK2 inhibitor therapy in a subject wherein the subject has at least one phosphorylated BAD- and/or activated BCL-XL protein.
  • the method includes the step of administering to the subject a therapeutically effective amount of a BCL-XL protein inhibitor, whereby the subject's resistance to the JAK2 inhibitor therapy is reversed.
  • the di sclosure encompasses a method of treating a subj ect having resistance to JAK2 inhibitor therapy and at least one phosphorylated BAD- and/or activated BCL-XL protein.
  • the method includes the step of administering to the subject a therapeutically effective amount of a BCL-XL protein inhibitor.
  • the th BCL-XL protein inhibitor is administered before or concurrently with the JAK2 inhibitor.
  • Exemplary BCL- protein inhibitors that can be used in the disclosed methods include without limitation ABT-737, ⁇ -263, ABT-199, Genasense, obatoelax, and combinations thereof.
  • the disclosure encompasses a method of predicting the response of a subject to a JAK2 inhibitor-based therapy.
  • the method includes the steps of obtaining a biological sample from the subject and determining the activation state of the AKT and/or ERK pathway in the subject. The presence of an activated AKT and/or ERK pathway is indicative of JAK2 inhibitor-based therapy resistance.
  • the disclosure encompasses a method of predicting the response of a subject to a JAK2 inhibitor-based therapy.
  • the method includes the steps of obtaining a biological sample from the subject and determining the activation state of at least one BAD protein and/or BCL-X L protein. The presence of phosphorylated BAD protein and/or activated BCL-XL protein is indicative of JAK2 inhibitor-based therapy resistance.
  • the biological sample is taken before, during, or after therapy.
  • Figure 1 Pathway activating ORE screen reveals potential modes of resistanee to
  • Staurosporine inhibits PrkA in vitro phosphorylation in a dose-dependent manner.
  • Autophosphorylation (arrow) and myelin basic protein (3VIBP) phosporylation (*) activity was assayed for PrkA (lanes 1-5), Lmo0618 (lanes 6-9), and S.a.Stkl (lanes 10-1 1) in the presence or absence of ⁇ ⁇ , 10 ⁇ or ⁇ staurosporine.
  • FIG. 3 Ras effector pathway activation confers resistance to JAK inhibition in an additional JAK2 V6in' positive cell line, Set2.
  • A Relative proliferation of Set2 cells transduced with the indicated constructs and treated with the indicated concentrations of INCB. Error bars show the SD of three replicate experiments.
  • B Same as in ( A) except cells were treated with CYT.
  • HEL92.1.7 cells were transduced with the indicated constructs and treated with the indicated concentrations of INCB. Error bars show the SD of three replicate experiments. [0064] Figure 5. Akt-mediated resistance to JAK inhibition occurs independently of downstream mTOR activity. HEL92.1.7 cells were transduced with the indicated constructs and treated with the indicated concentrations of INCB, alone or in combination with a dual
  • Percent depolarization is shown as the area under the curve (AUG) normalized to positive control fully depolarized mitochondria (FCCP).
  • DM SO serves as the negative control.
  • Data shown are representative of three independent experiments for each cell line derivative.
  • C Same as in (B) except in this ease the indicated JAK2 V61 ⁇ ' positive cell lines were profiled to query their apoptotic dependencies.
  • D Lysates from HEL92.1.7 cells were immunoblotted as indicated after treatment with INCB for 6 hours. B lots are representative of three replicate experiments.
  • E Twenty-four hours after transduction with the indicated ORFs, HMLE and HBL92.1.7 cells were stained with 7AAD and Annexin V to measure induction of apoptosis. Error bars indicate SD of three replicate experiments.
  • F A model depicting the putative signaling axis downstream of mutant JAK2. ***p ⁇ 0.001 by Student's t test.
  • HEL92.1.7 cells transduced with the indicated constructs were stained with the mitochondrial potential-sensitive JCl dye, incubated with a panel of BH3 peptides at the indicated
  • Mitochondrial priming profiles were generated for HEL control (A), Akt (B), and Ras (C) expressing cells. Data shown are representative of three independent experiments for each cell line derivative.
  • FIG. 9 BH3 profiling indicates that HMLE cells are not depolarized by BAD peptide and thus not dependent on BCL-2/BCL-XL.
  • A Similar to Fig. 6B except in HMLE cells.
  • B Mitochondrial depolarization over time in HMLE cells, similar to Fig, 7.
  • FIG. 10 BAD activity, governed by phosphorylation status at Ser 112 and 136, dictates drug sensitivity and induction of apoptosis in both the drug-sensitive and resistant state.
  • A-C After 6 hours of treatment with the specified drugs, protein lysates were prepared from either myr-Akt-transduced HEL92.1.7 (A), Ras (G12V transduced HEL92.1.7 (B), Set2- Parental, or Set2 ⁇ CYTR cells (C) and immunoblotted with the indicated antibodies. Blots are representative of three replicate experiments.
  • D INCB GI5G values for HEL92.1.7 cells expressing the indicated short hairpin vectors; protei knockdown assessed 72 hours after lentiviral transduction and selection (inset).
  • FIG. 1 BCL-XL, not BCL-2 or MCL-1 , is the key anti-apoptotic effector downstream of JA and BAD.
  • A HEL92.1.7 cells were treated with INCB for 6 hours and immunoblotted as shown. Blots are representative of three replicate experiments.
  • B
  • HEL92.1.7 ORF-expressing derivatives were treated with either a selective BCL-2 inhibitor (ABT-199), a selective BCL-X L inhibitor (WEHL539), or BCL-tamily inhibitor (ABT-737) for 48 hours and then stained with 7AAD and Annexin V to measure the induction of apoptosis. Error bars indicate SEM of three replicate experiments (Below and Right). As in Fig. 2A, the relative proliferation for the indicated HEL92.1.7 derivatives or Set2-Parenta;l, -FNCBR, and - CYTR cell lines treated with the specified inhibitors is shown. Error bars indicate SD of "three replicate experiments. (C) HEL92.1.7.
  • FIG. 12 An additional JAK2 V617h positive ceil line, Set2, shows sensitivity to inhibition of BCL-XL, but not BCL-2.
  • A-C Relative proliferation of Set2 ORF-expressing derivatives were treated with either a selective BCL-2 (ABT-199; A), BCL-family (ABT-737; B), or a selective BCL-Xi. (WEHI-539; C) inhibitor. Error bars indicate SD of three replicate experiments.
  • FIG. 13 A B AD/BCL-X L -centric model governing survival in JAK inhibitor- resistant and sensitive cells. In the sensitive state (grey dashed line), survival is predominantly
  • Ras effector pathways ERK and Akt driven by activating mutations in Ras or other upstream signals, provide compensatory survival signals at the functionally equivalent Ser 112 and 136 sites, rescuing the effects of JAK2 inhibition and representing a coalescent signaling node through which survival is orchestrated ⁇ n JAK2 V6l7F cells.
  • administering refers to bringing a subject, tissue, organ or cells in contact with one or more of the inhibitor described in this disclosure.
  • the present invention encompasses administering the compounds useful in the present invention to a patient or subject.
  • cancer refers to any of those diseases characterized by an uncontrolled division and growth of abnormal cells in the body. Examples include* but are not limited to, myeloproliferative disorders such as polycythemia vera (PCV), essential thrombocythemia (ET), primary myelofibrosis (PMF), chronic eosinophilic leukemia (CEL), chronic myelomonoeytic leukemia (CMML), systemic mastocytosis (SM) and idiopathic myelofibrosis (IMF); leukemia such as myeloid leukemia including chronic myeloid leukemia (CML), imatinii resistant forms of CML, acute myeloid leukemia (AML), and a subtype of AML, acute megakaryoblastic leukemia (AMKL); lymphoproliferative diseases such as myeloma; cancer such as cancer of the head and neck, prostate cancer, breast cancer, ovarian cancer
  • PCV polycythemia vera
  • treatment refers to the clinical intervention made in response to a disease, disorder or physiological condition manifested by a patient or to which a patient may be susceptible.
  • the aim of treatment include the alleviation or prevention of symptoms, slowing or stopping the progression or worsening of a disease, disorder, or conditio and/or the remission of the disease, disorder or condition.
  • treatments for cancers may include the use of anti-cancer/chemotherapeutic agents (e.g., anti-metabolites (e.g., 5-fluoiO-uracil, methotrexate, fludarabine), antimicrotubule agents (e.g., vinca alkaloids such as vincristine, vinblastine; taxanes such as paeiitaxel, docetaxel), alkylating agents (e.g., cyclophosphamide, melphalan, earmustine, nitrosoureas such as bischloroethylnitrosurea and hydroxyurea), platinum agents (e.g., anti-cancer/chemotherapeutic agents (e.g., anti-metabolites (e.g., 5-fluoiO-uracil, methotrexate, fludarabine), antimicrotubule agents (e.g., vinca alkaloids such as vincristine, vinblastine; taxanes such as paeiitaxel, docet
  • eisplatin carboplatin, oxaliplatin, JM-216 or satraplatin, CI-973
  • anthracyclines e.g., doxrubicin, daunorubicin
  • antitumor antibiotics e.g., mitomycin, idarubicin, adriamycin, daunomycin
  • topoisomerase inhibitors e.g., etoposide, camptothecins
  • anti-angiogenesis agents e.g. Sutent 1 M and
  • cancers comprising a JAK2 V617F mutation may include, but are not limited to, treatment with drugs that inhibit JAK2 activity (e.g., INCBO 18424). Such treatments are well known and particular to the patient and can be readily determined by one skilled in the art.
  • the term "effective amount” or “therapeutically effective amount” refers to an amount sufficient to effect beneficial or desirable biological and/or clinical results.
  • the specific "effective amount” will, obviously, vary with such factors as the particular condition being treated, the physical condition of the patient, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulations employed.
  • the optimum effective amounts can be readily determined by one of ordinary skill in the art using routine
  • the term “subject” and “patient” are used interchangeably herein and refer to both human and nonhuman animals.
  • the term “nonhuman animals” of the disclosure includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dog, cat, horse, cow, chickens, amphibians, reptiles, and the like.
  • the subject is a human patient that is at for, or suffering from, a cancer.
  • biological sample includes, but is not limited to, a sample containing tissues, cells, and/or biological fluids Isolated from a subject.
  • biological samples include, but are not limited to, tissues, cells, biopsies, blood, lymph, serum, plasma, urine, saliva, mucus and tears.
  • the biological sample Is a blood sample (such as a plasma sample) or biopsy sample (such as a tissue/cell sample).
  • the biological sample comprises cells.
  • the biological sample comprises blood,
  • a biological sample may be obtained directly from a subject (e.g., by blood or tissue sampling) or from a third party (e.g., received from an intermediary, such as a healthcare provider or lab technician).
  • the biological sample is taken before, during, and/or after the administration of the JAK2 inhibitor-based therapy.
  • a "JAK2 inhibitor,” as used herein, includes any compound that disrupts JAK2 production and or the JAK/STAT signaling pathway.
  • Cytokines play key roles in controlling cell growth and the immune response. Many cytokines function by binding to, and activating cytokine receptors found on the cell surface. These receptors in turn rely on the Janus kinase (JAK) family of enzymes for signal transduction. Specifically, Janus kinases phosphor late activated cytokine receptors which in turn recruit STAT transcription factors that modulate gene transcription. Hence, JAK inhibitors, and specifically JAK2 inhibitors, block cytokine signaling.
  • JAK2 inhibitors include, but are not limited to, INCBO 18424 (also known as Ruxolitinib), Tofacitinub, Baricitnib, CYT387, Lestaurtinib, Pacritinib, TG101348 and the like.
  • An "AKT and/or PI3K inhibitor,” as used herein, includes any compound that disrupts AKT production/activity, PI3K production activity, and or the AKT PI3K signaling pathway.
  • AKT1 inhibitors include, but are not limited to, AZD5363, VQD-002, Perifosine, Wortmannin, demthozyviridin, LY294002, CALIOI, PX-866, IPI-145, BAY 80- 6946, BEX235, RP6503, TGR 1202, SF1 126, INK!
  • An "ERK/MEK inhibitor,” as used herein, includes any compound that disrupts mitogen-activated protein kinase enzymes (MEKl and/or MEK2) or ERK production and or the MEK/ERK signaling pathway.
  • the MEK signaling pathway is a chain of proteins in a cell that communicate a signal from a receptor on the cell surface to the DNA in the nucleus.
  • ME l and MEK2 function by phosphorylating proteins in the Ras-Raf-MEK-ERK signaling pathway, thereby turning the pathway "on” and “off.” Whe one of the proteins is mutated, it can be stuck in the "on” or “off position, thereby leading to the development of cancer.
  • Examples of MEK inhibitors include, but are not limited to, Trametinib, Selumetinib, MEKl 62, PD-32590I , XL518, CI- 1040, PD035901 and the like.
  • BCL-family inhibitor includes any inhibito capable of disrupting or inhibiting the anti-apoptotic proteins of the BCL signaling pathway.
  • the BCL signaling pathway governs mitochondrial outer membrane pefmeabilization and can be either pro-apoptotic (includes family members Bax, BAD, Bak, and Bok among others) or anti- apoptotic (including Bcl-2, BcI-xL, and Bcl-w, among others).
  • pro-apoptotic include, but are not limited to, ABT-737, ABT-263, ABT-199, Genasense, obatoclax, and combinations thereof.
  • the term "in combination” refers to the use of more than one therapeutic agent (e.g., a JAK2 inhbitor and a BLC-family inhibitor or an AKT and/or PI3K inhibitor and/or MEK inhibitor).
  • a therapeutic agent e.g., a JAK2 inhbitor and a BLC-family inhibitor or an AKT and/or PI3K inhibitor and/or MEK inhibitor.
  • the use of the term “in combination” does not restrict the order i which said therapeutic agents are administered to a subject with a disease or disorder, e.g., a cancer.
  • one method of the present disclosure provides a method of predicting the response of a subj ect to a JAK2 inhibitor-based therapy comprising, consisting of, or consisting essentially of obtaining a biological sample from the subject and determining the activation state of the AKT and/or ERK pathway, wherein the presence of an activated AKT and/or ERK pathway is indicative of JAK2 inhibitor-based therapy resistance.
  • Another method of the present disclosure provides a method of predicting the response of a subject to a JAK2 inhibitor-based therapy comprising, consisting of, or consisting essentially of obtaining a biological sample from the subject and determining the activation state of at least one BAD protein and/or BCL-XL protein, wherein the presence of phosphorylated BAD protein and/or activated BCL-XL protein is indicative of JAK2 inhibitor-based therapy resistance.
  • the method further comprises determining the presence of
  • the method further comprises detemiining the presence of phosphorylated BAD protein and/or activated BCL-XL protein.
  • Some of the disclosed methods ca be particularly effective at treating subjects whose cancer has become “drug resistant” or “multi-drug, resistant. " A cancer which initially responded to an anti-cancer drug, such as a JAK2 inhibitor, becomes resistant to that anticancer drug when the anti-cancer drug is no longer effective in treating the subject with the cancer. For example, many tumors will initially respond to treatment with an anticancer drug by decreasing in size or even going into remission, onl to develop resistance to the drug. "Drug resistant” tumors are characterized by a resumption of their growth and/or reappearance after having seemingly gone into remission, despite the administration of increased dosages of the anti-cancer drug.
  • Cancers that have developed resistance to two or more anticancer drugs are said to be "multi-drug resistant.” For example, it is common for cancers to become resistant to three or more anti-cancer agents, often five or more anti-cancer agents and at times ten or more anti-cancer agents.
  • JAK2 inhibitor therapy resistance includes the acti vation in AKT and/or H-Ras activity and phosphorylation of B AD and/or acti vated BCL-XL proteins that allow for the reactivation of pro-survival pathways that were once inhibited by the JAK2 inhibitor. Targeting these mechanisms has therapeutic value.
  • another aspect of the present disclosure provides a method of sensitizing a subject to a JAK2 inhibitor wherein the subject has developed resistance to a JAK2 inhibitor-based therapy and has an activated AKT pathway comprising, consisting of, or consisting essentially of administering to the subject a therapeutically effective amount of an AKT and/or P13K inhibitor in combination with the JAK2 inhibitor.
  • Another aspect of the resent disclosure provides a method of reversing resistance to JAK2 inhibitor therapy in a subject wherei the subject has an activated AKT pathway comprising, consisting of, or consisting essentially of administering to the subject a therapeutically effective amount of an AKT and/or PI3K inhibitor in combination with the JAK2 inhibitor.
  • the AKT and/or PI3K inhibitor is administered before or concurrently with the JAK2 inhibitor.
  • Another aspect of the present disclosure provides a method of sensitizing a subject to a JAK2 inhibitor wherein the subject has developed resistance to a JAK2 inhibitor- based therapy and has an activated ERK pathway comprising administering to the subject a therapeutically effective amount of an ERK/MEK inhibitor in combination with the JAK2 inhibitor.
  • Yet another aspect of the present disclosure provi des a method of reversing resistance to JAK2 inhibitor therapy in a subject wherein the subject has an activated ERK/MEK pathway comprising, consisting of, or consisting essentially of administering to the subject a therapeutically effective amount of an ERK MEK inhibitor in combination with the JAK2 inhibitor.
  • the ERK MEK inhibitor is administered before or concurrently with the JAK2 inhibitor.
  • Another aspect of the present disclosure provides method of sensitizing a subject to a JAK2 inhibitor wherein the subject has developed resistant to a JAK2 inhibitor-based therapy and has an activated ATK and ERK pathway comprising, consisting of, or consisting essentially of administering to the subject a therapeutically effective amount of an AKT and/or PI3K inhibitor and an ERK/MEK inhibitor in combination with the JAK2 inhibitor.
  • Yet another aspect of the present disclosure provides a method of reversing resistance to JAK2 inhibitor therapy i a subject wherein the subject has an activated AKT and ERK MEK pathway comprising, consisting of, or consisting essentially of administering to the subject a therapeutically effective amount of an AKT and/or PI3K inhibitor and an ERK/MEK inhibitor in combination with the JAK2 inhibitor.
  • the AKT and/or PBK inhibitor and the ERK/MEK inhibitor are administered before or concurrently with the JAK2 inhibitor.
  • Another aspect of the present disclosure provides a method of sensitizing a subject to a JA 2 inhibitor wherein the subject has developed resistance to a JAK2 inhibitor- based therapy and has at least one phosphorylated BAD protein and or activated BCL-XL protein comprising, consisting of, or consisting essentially of administering to the subject a
  • Another aspect of the present disclosure provides a method of reversing resistance to JAK2 inhibitor therapy in a subject wherein the subject has at least one phosphorylated BAD- and/or activated BCL- XL protein comprising, consisting of, or consisting essentially of administering to the subject a therapeutically effective amount of a BCL- XL protein inhibitor.
  • BCL-XL protein inhibitors have a beneficial therapeutic effect even in the absence of the a JA 2 inhibitor in these resistant cancer cells. Accordingly, another aspect of the present disclosure provides a method of treating a subject having resistance to JAK2 inhibitor therapy and at least one phosphorylated BAD protein and/or activated BCL-XL protein comprising, consisting of, or consisting essentially of administering to the subject a therapeutically effective amount of a BCL-XL protein inhibitor.
  • the BCL-farnily inhibitor or the AKT and/or PI3K and/or ME inhibitor is administed prior to, or concurrently with, the JAK2 inhibitor.
  • a first inhibitor such as a BCL- family inhibitor or an AK and/or P13 and/or MEi inhibitor
  • a first inhibitor can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before) or concomitantly with the administration of a JAK2 inhibitor to a subject with a disease or disorder, e.g. a proliferative disorder, such as cancer,
  • the BCL-family inhibitor or the AKT and/or PI3K and/or MEK inhibitor and the J AK2 inhibitor are dosed on independent schedules. In another embodiment, the BCL-family inhibitor or the AKT and/or PI3K inhibitor and/or the MEK inhibitor and the JAK2 inhibitor are dosed on approximately the same schedule. In another embodiment, the BCL-family inhibitor or the AKT and/or PI3K and/or MEK inhibitor and the JAK2 inhibitor are dosed concurrently or sequentially on the same day. [00111]
  • the disclosure also provides pharmaceutical compositions comprising one or more of the disclosed inhibitors i association with a pharmaceutically acceptable carrier.
  • compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. It is also envisioned that the compounds of the present invention may be incorporated into transdermal patches designed to deliver the appropriate amount of the drug in a continuous fashion.
  • the principal active ingredient is mixed with a pharmaceutically acceptable carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation
  • a pharmaceutically acceptable carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation
  • compositions containing a homogeneous mixtur e for a compound of the present invention, or a pharmaceutically acceptable salt thereof When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be easily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid pre-formulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
  • Typical unit dosage forms contain from 1 to 100 mg, for example, 1 , 2, 5 , 10, 25, 50 or 100 mg, of the active ingredient.
  • the tablets or pills can be coated or otherwise compounded to provide a dosage affording the advantage of prolonged action.
  • the tablet or pill can comprise an inne dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which, serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • the liquid forms in which the composi tion of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium caboxymethylcellulo.se,
  • Example 1 Ras effector pathways drive resistance to JAK inhibitors by suppressing BAD- mediated apoptosis
  • JAK2 -mediated inactivating phosphorylation of the pro-apoptotic protein B AD is controlled by JAK2 -mediated inactivating phosphorylation of the pro-apoptotic protein B AD.
  • BAD is dephosphorylated, allowing it to bind and sequester the pro-survival protein BCL-X L> triggering apoptosis
  • Ras effector pathways drive resistance b maintaining BAD phosphorylation in the presence of JAK inhibitors, yielding a specific dependence on BCL-XL for survival.
  • BCL-XL inhibitors potently induce apoptosis in JAK inhibitor-resistant cells.
  • myeloproliferative neoplasms (MPNs,(i-5)), a class of hematologic malignancies arising from hematopoietic progenitors that includes acute and chronic myeloid leukaemias, polycythaemia vera, essential thrombocythaemia and primary myelofibrosis.
  • JAK kinase inhibitors such as TG101348 (SAR3Q2503), INCB018424 (Ruxolitinib), and CYT387 (4-6).
  • JAK inhibitors were found to produce palliative effects associated with decreased inflammatory cytokine abundance and reduced splenomegaly but were unable to reverse the disease by decreasing the malignant clone burden (7, 8).
  • JAK inhibitor therap to reduce or eliminate the MPN clone may be caused by a number of factors, including: (i) second site mutations in the JAK2 kinase domain which block effective drug binding to its target (9); (ii) the reactivation of JAK-STAT signaling in the presence of JAK inhibitors, for example through the heterodimerization of J AK2 with JAK1 or TYK2, (10); and (iii) the activation of compensatory signaling pathways which enable malignant cells to circum ven the toxic effects of JAK inhibition.
  • Informative studies were recently conducted to examine options (?) and (ii) above, indicating that these mechanisms may contribute to the resistance observed in some patients. However, despite considerable evidence that compensatory signaling pathways can contribute to resistance to anticancer drugs, including kinase targeted therapies (11-14), no studies have systematically assessed the potential roles of such pathways in the resistance of MPNs to JAK inhibitors.
  • Ras effector pathways are capable of conferring resistance to JAK inhibition.
  • Activators of 17 oncogenic signaling pathways were screened in JAKf 6! 7 UKE-l cells to identify those capable of driving resistance to INCBGi8424 (1NCB). Screens were performed using low multiplicity of infection (MOI) conditions to ensure that only a single transgene pathway activator was introduced into each cell Further, a moderate strength promoter (PGK) was used to minimize the likelihood of superphysiOlogical pathway activation owing to overexpression (15).
  • MOI multiplicity of infection
  • PGK moderate strength promoter
  • Estrogen ERa (Y537S bogen Lab, NM_000125.3 * Reporter receptor mutant) UJ ' UC human variant 1 Yes (ERE_Luc)
  • Akt and Ras activation also conferred resistanee to the direct knockdown of JAK2 by two independent shJAK2 constructs (Fig. 2B), suggesting that, unlike the recently reported JA 2-JA 1/JA 2-Tyk2 heterodimerization phenomenon (10% Akt- and Ras-driven resistance can operate independently of JAK2 expression.
  • constmcts from the NF-KB and Notch pathways also scored weakly in the primary screen ( ⁇ 3 fold enrichment; Fig. 1) but failed to confer robust resistance to INCB in subsequent GI50 validation assays (Fig, 4).
  • Akt and Ras constructs are acti vators of Ras effector pathways, a diverse set of pathways that have been implicated extensively in cell growth and survival processes downstream of activated Ras (16).
  • Akt-expressing cells could be fully resensitized to INCB using an allosteric Akt inhibitor, MK-2206 (Fig, 2C), but not by using BEZ-235, a dual PI3K mTOR inhibitor, suggesting that resistance in these cells does not depend on Akt-mediated mTOR activation (Fig. 5) .
  • Ras-expressing cells could be resensitized by dual inhibition of the ERK and Akt effector pathways (using the ERK inhibitor VX-1 IE and MK-2206, respectively), but not by inhibition of either pathway alone, suggesting that Ras-driven resistance involves the concerted activation of these two effector pathways (Fig, 2D),
  • Table 2 Patient cohort information.
  • Akt inhibition using MK-2206 re- sensitized both Set2-CYTR and Sei2-INCBR cells to parental GI50 values, and co-inhibition of both the Akt and ERK effector pathways (the latter using the mitogen-activated protein kinase 1 and 2 (MEK1/2) inhibitor AZD-6244) further sensitized both resistant and parental cells.
  • JAK inhihitor-induced apoptosis is normally stimulated by BAD in JAK2 V6!7F cells
  • JAK2 m7F cells we performed BH3 profiling (1 -iP).
  • cells are permeabiiized, stained with a mitochondrial-potential sensiti e dye, and treated with peptides derived from the BH3 domains of pro-apoptotic BH3-only proteins.
  • BH3 peptides can bind and inactivate specific anti-apoptotic proteins, triggering mitochondrial outer membrane permeabillzation (MOMP) and mitochondrial depolarization in cells dependent on those proteins.
  • BH3 profiling can measure overall priming for apoptosis (20) or identify dependence on specific anti-apoptotic proteins.
  • Ras effector pathways drive resistance by blocking DAD-indiiced apoptosis.
  • Akt and ERK Activation of the Ras effector pathways Akt and ERK leads to inhibitory phosphorylation of BAD at Ser 136 and 1 12, respectively, independent of PIMl (22, 25).
  • BAD phosphorylation in Akt- or Ras-expressing cells in the presence of INCB.
  • Akt-expressing cells phosphorylation of Ser Ij6 was enhanced by Akt activation both in the presence and absence of INC B; this phosphorylation was reversed by treatment with an Akt inhibitor (Fig.. 10A).
  • BCL-X is the relevant cmti-apoptotic target downstream of JAK and BAD. [00143] BAD can potentially bind and inactivate BCL-2, BCL-X L , and BCL-w (19).
  • Resistance to JAK inhibition can thus be driven by Ras effector-mediated suppression of the BAD/BCL-XL signaling axis, and reciprocally, resistance can be inhibited by either co-inhibition of JA and the Ras effector pathways Akt and ERK or by direct inhibition of
  • BAD phosphorylation at Ser 5 12 is the relevant target of JAK/STAT signaling in drug sensitive cells; that BAD phosphorylation at Ser 112 and 136 by the Ras effectors ERK and Akt, respectively, can rescue JAK inhibitior-induced loss of Ser phosphorylation; and finally, that BAD phosphorylation is required for survival and Ras effector-mediated drug resistance.
  • BIM is necessary for the executio of apoptosis via its efficient activation of BAX (38% and its knockdown is sufficient to drive resistance to JAK inhibitors (37), but it acts downstream of BAD.
  • UKE-1 and HEL92.1.7 cells were obtained from Ann Mullally, Brigham and Women's Hospital, and Set2 parental and resistant cell lines were obtained from Ross Levine, Memorial Sloan-Kettering. Drugs were purchased from Selleck Chemicals, ChemieTek, and ApexBio and were used at the following concentrations: 2 ⁇ for VX-1 I E, 10 ⁇ for MK-2206, 2 ⁇ for AZD-6244, 0.2 ⁇ for BEZ-235 (GI50 assay and western blots), 4 ⁇ for SGl-1776 (western blots and apoptosis assays), 1 ⁇ for INCB and CYT (western Wots, BH3 profiling), and 5 ⁇ for INCB, 1.6 ⁇ for ABT-737 and ABT-199, and 0.8 ⁇ for WEHI-539 (apoptosis assays).
  • GI50 curves To generate GI50 curves, cells were treated with vehicle (DMSO) or an eight-log serial dilution of drug to yield final concentrations of 200, 20, 2, 0.2, 0.02, 0.002, 0.0002, or 0.00002 ⁇ . Each treatment condition was represented by at least three replicates. Three to four days after drug addition, cell viability was measured using Cell Titer Glo® (Promega). Relative viability was then calculated by nonnalizing luminescence values for each treatment condition to control treated wells.
  • vehicle DMSO
  • 0.02, 0.002, 0.0002, or 0.00002 ⁇ Each treatment condition was represented by at least three replicates. Three to four days after drug addition, cell viability was measured using Cell Titer Glo® (Promega). Relative viability was then calculated by nonnalizing luminescence values for each treatment condition to control treated wells.
  • TRC shRNA clones were obtained from Sigma-Aldrich and the Duke R Ai Facilit as glycerol stocks. Constmcts were prepared in lentiviral form and used to infect target cells as previously described (43).
  • Gatings were defined usin untreated/unstained cells as appropriate.
  • Wild-type and double Ser-to-Ala (SI 12A/S136A) mutant murine BAD constructs were obtained from Addgene and cloned using the Gateway® system (Life Technologies) into the pLX-303 vector and prepared for lenti vital infection as previously described (44).
  • the patient cohort consisted of 42 patients.
  • the male to female ratio was 1 ,8 (27/15),
  • the media age was 75.9 years, ranging from 55.3 to 89.1 years. All patients were diagnosed following the WHO 2008 criteria, includedin 16 cases with Chronic myelomonocytic leukemia (CMML), 2 with Myelodysplastic/myeloproliferative neoplasm, unclassifiable
  • CMML Chronic myelomonocytic leukemia
  • Myelodysplastic/myeloproliferative neoplasm unclassifiable
  • MDS/MPN, U 6 with MPN and 18 with Refractory anemia with ring sideroblasts and thrombocytosis (RARS -T) .
  • RARS -T Refractory anemia with ring sideroblasts and thrombocytosis
  • V617F mutation was analyzed by melting curve analysis, as described in Thomasger et al. (45) NRAS mutation were analyzed either by melting curve analysis described previously (46) or Next-generation deep-sequencing using the 454 GS FLX amplicon chemistry (Roche Applied Science) as previously described (47). In melting curve analysis positive NRAS cases were subsequently further characterized by Next-generation sequencing. KRAS mutations were either sequenced by the Sanger method or Next-generation deep-sequencing (45, 47),
  • BH3 profiling identifies three distinct classes of apoptotic blocks to predict response to ABT-737 and conventional chemotherapeutic agents. Cancer cell 12, 171-185 (2007), M, Certo, V. Del Gaizo Moore, M. Nishino, G. Wei, S. Korsmeyer, S. A. Armstrong, A. Letai, Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer cell 9, 351-365 (2006). A. G. Letai, Diagnosing and exploiting cancer's addictio to blocks in apoptosis. Nature reviews: Cancer $, 121-132 (2008). T. Ni Chonghaile, . A. Sarosiek, T. T.
  • Zinda Effects of the JAK2 inhibitor, AZ960, on Pim/BAD/BCL-xL survival signaling in the human JAK2 V J7F cell line SET-2.
  • B Will, T. Siddiqi, M. A. Jorda, T, Shimamura, K. Luptakova, P. B. Staber, D. B. Costa, U, Steidl, D. G. Tenen, S. Kobayasbi, Apoptosis induced by JAK2 inhibition is mediated by Bim and enhanced by the BH3 mimetic ABT-737 in JAK2 mutant human erytliroid cells.

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Abstract

Cette invention concerne des méthodes et des compositions destinées à diagnostiquer et à traiter les cancers résistant à l'inhibiteur JAK2. Dans les méthodes décrites, des inhibiteurs d'AKT et/ou de PI3K, des inhibiteurs d'ERK/MEK, des inhibiteurs de protéines BCL-XL, ou leurs combinaisons sont administrés à un sujet pour inverser sa résistance à l'inhibiteur JAK2. Par conséquent, les compositions contenant ces inhibiteurs peuvent être utilisées avec des inhibiteurs JAK2 pour traiter avec succès les cancers résistant à l'inhibiteur JAK2.
PCT/US2014/059045 2013-10-03 2014-10-03 Compositions et méthodes destinées à traiter les cancers ayant une activité jak2 WO2015051252A1 (fr)

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US11801237B2 (en) 2019-12-30 2023-10-31 Deciphera Pharmaceuticals, Llc Amorphous kinase inhibitor formulations and methods of use thereof
US11969415B1 (en) 2019-12-30 2024-04-30 Deciphera Pharmaceuticals, Llc (methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11793795B2 (en) 2019-12-30 2023-10-24 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea
WO2022074599A1 (fr) * 2020-10-08 2022-04-14 Novartis Ag Utilisation d'un inhibiteur d'erk pour le traitement de la myélofibrose
WO2022074600A1 (fr) * 2020-10-08 2022-04-14 Novartis Ag Utilisation d'un inhibiteur d'erk pour le traitement de la myélofibrose
WO2023245160A1 (fr) * 2022-06-16 2023-12-21 Astrid Pharma Corp. Méthodes et compositions de nanoparticules immunomodulatrices quaternaires pour applications médicales et immunothérapie

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